1-phenoxy-3-amino-2-propanols use thereof

ABSTRACT

Compounds of formula ##STR1## (the substituents R 1 , R 2 , R 3 , R 4  and R 5  are explained in the specification) may be prepared by conventional methods. 
     Owing to their favorable activity profile the compounds may advantageously be used to treat certain heart and circulatory disorders.

The invention relates to 1-aryloxy-3-amino-2-propanols, the preparationthereof in a manner known per se and their use as pharmaceuticalcompositions.

The new compounds are of the formula ##STR2## wherein R₁ represents aphenyl group which may optionally be substituted by one or more halogenatoms, lower alkyl, alkoxy, alkenyl, alkynyl, alkenyloxy, alkynyloxy,cycloalkyl, acyl, acyloxy, alkoxycarbonyl, hydroxyalkyl or alkoxyalkylgroups or a sulphamoyl group or the ring-binding groups --(CH═CH)₂ --,--O--CH₂ --O--, with bonding of the free valencies in the o-positionrelative to one another, or it may represent an aryloxyalkyl group whichmay optionally be substituted by one or more halogen atoms, lower alkyl,alkoxy, alkenyl, alkynyl, alkenyloxy, alkynyloxy, hydroxyalkyl,alkoxyalkyl, acyl, acyloxy or alkoxycarbonyl groups and the ring-forminggroup --(CH═CH)₂ -- or --OCH₂ --O-- with bonding of the free valenciesin the o-position relative to one another, or a pyridyl group, or ananilino group which may be substituted by one or more halogen atoms orlower alkyl groups,

R₂ represents a hydrogen or halogen atom, an alkyl or alkoxy group with1 to 4 carbon atoms or the ring-forming groups --(CH═CH)₂ -- or--(CH₂)_(n) -- (n=an integer from 3 to 5) with bonding of the freevalencies in the o-position relative to one another, or a CN group,

R₃ represents a hydrogen or halogen atom or an alkyl group with 1 to 4carbon atoms,

R₄ represents a straight-chained or branched alkyl group with 1 to 10carbon atoms or a hydroxyalkyl group with 2 to 5 carbon atoms, and

R₅ represents a straight-chained or branched alkyl group with 1 to 10carbon atoms or a hydroxyalkyl group with 2 to 5 carbon atoms or aphenylalkyl group or a phenoxyalkyl group, wherein the aromatic part maybe substituted by alkyl or alkoxy groups or by chlorine or bromineatoms, or

R₄ and R₅ may also together with the nitrogen atom represent aheterocyclic group, e.g. a morpholine, piperidine or piperazine ring,

and they may occur in the form of racemates, pure enantiomers ormixtures of enantiomers and the acid addition salts thereof.

Unless otherwise specifically stated, the general definitions are usedin the following sense.

The "lower" alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy and alkynyloxygroups contain up to 4 carbon atoms, as do the carbon chains in theacyl, acyloxy, alkoxycarbonyl, hydroxyalkyl or alkoxyalkyl groups. Thecycloalkyl groups contain 3 to 8, preferably 5 to 7 carbon atoms. "Aryl"indicates phenyl and naphthyl, in compositions as well. "Halogen"indicates chlorine and also bromine and fluorine and, to a lesserextent, iodine.

The groups of the type specified are therefore methyl, ethyl, n-propyl,i-propyl, the butyls, allyl, propargyl and the associated -oxy groups,acyl groups such as CH₃ CO, C₂ H₅ --CO and corresponding acyloxy group,alkoxycarbonyl groups such as COOC₂ H₅, COOCH₃, COOC₃ H₇, alkoxyalkylgroup such as C₂ H₅ OC₂ H₄, H₃ C--O--CH₂ --CH₂ --, C₃ H₇ OCH₂, andcycloalkyl groups such as cyclopentyl and cyclohexyl.

R₁ preferably represents substituted phenoxymethyl groups.

R₂ and R₃ preferably represent halogen and methyl.

R₄ and R₅ preferably represent lower straight-chained or branched alkylgroups, particularly the methyl, ethyl, n-propyl or i-propyl group.

The new compounds may be prepared in a manner known per se by reacting acompound of general formula ##STR3## wherein R₁, R₂ and R₃ are definedas in formula I and Z represents the group ##STR4## or --CHOH--CH₂ --Hal(Hal=halogen, e.g. Cl or Br), with an amine of formula ##STR5## whereinR₄ and R₅ are defined as hereinbefore.

If acid addition salts are initially obtained, these are optionallyconverted by conventional methods into free bases or salts of otheracids. If bases are obtained initially they may, if desired, beconverted into acid addition salts.

The process is preferably carried out at temperatures between 0° and100° C., more particulally at 4° to 80° C.

The reaction media used may be alcohol or other polar solvents, e.g.methanol, ethanol, isopropanol, dioxan or tetrahydrofuran, optionally inadmixture.

The starting compounds for the process according to the invention arealready known or may be prepared by known methods.

The compounds according to the invention at least one asymmetric carbonatom (at the CHOH group) therefore may occur as racemates and also theform of the optical antipodes. The latter may be obtained not only byracemate separation but also with conventional auxiliary acids such asdibenzoyl (or di-p-tolyl) D-tartaric acid orD-3-bromocamphor-8-sulphonic acid or by the use of optically activestarting material.

Suitable acids for the preparation of physiologically acceptable acidaddition salts include, for example, hydrochloric, hydrobromic,sulphuric, methanesulphonic, maleic, acetic, oxalic, lactic or tartaricacid or 8-chlorotheophylline.

The new compounds and the physiologically acceptable acid addition saltsthereof have valuable therapeutic, particularly antiarrhythmic,hypotensive or bradycardiac properties and may, on the basis of theirfavourable activity profile, be used advantageously, for example, totreat cardiac arrhythmia, tachycardia or high blood pressure in humanmedicine.

Those compounds of general formula I wherein R₁ represents a substitutedphenoxymethyl group and NR₄ R₅ represents a dimethylamino group, amethylethylamino group or a dimethylamino group (substitutedp-phenoxyacetylaminophenoxy-3-diethyl, -methylethyl- or-dimethylamino-2-propanols) have Proved Particularly useful.Particularly valuable compounds are

1-[2,6 dimethyl 4-(2-(2,6dimethyl-phenoxy)-acetylaminophenoxy]-2-hydroxy-3-diethylaminopropane

and1-[2,6-dimethyl-4-(2-m-tolyloxy-acetylamino)-phenoxy]-2-hydroxy-3-diethylamino-propane.

The single dosage of the substances according to the invention is from 1to 300 mg, preferably 10 to 150 mg (by oral route) or 1 to 20 mg (byparenteral route).

The active substances according to the invention may be made intoconventional pharmaceutical preparations such as plain or coatedtablets, solutions, emulsions, powders, capsules or delayed releaseforms, and may be produced using the normal pharmaceutical excipientsand the usual methods of manufacture.

Tablets may be produced, for example, by mixing the active substance orsubstances with known excipients, e.g. inert diluents such as calciumcarbonate, calcium phosphate or lactose, disintegrants such as cornstarch or alginic acid, binders such as starch or gelatine, lubricantssuch as magnesium stearate or talc and/or agents for obtaining delayedrelease such as carboxymethylcellulose, cellulose acetate phthalate orpolyvinyl acetate.

The tablets may also consist of several layers. Coated tablets may beproduced accordingly by coating cores made in the same way as thetablets with the substances normally used for tablet coating, such ascollidone or shellac, gum arabic, talc, titanium dioxide or sugar. Inorder to obtain delayed release or prevent incompatibilities, the coremay also consist of several layers. Similarly, the tablet coating mayconsist of several layers in order to obtain delayed release, and theexcipients mentioned above for the tablets may be used.

Syrups of the active substances or combinations of active substancesaccording to the invention may additionally contain a sweetener such assaccharin, cyclamate, glycerol or sugar and a flavour-enhancing agent,e.g. a flavouring such as vanillin or orange extract. They may alsocontain suspension adjuvants or thickeners such as sodiumcarboxymethylcellulose, wetting agents, e.g. condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Injection solutions are prepared in the usual way, e.g. by addingpreservatives such as p-hydroxybenzoates or stabilizers such ascomplexones and the resulting solutions are transferred into injectionvials or ampoules.

Capsules containing one or more active substances or combinations ofactive substances may be Prepared, for example, by mixing the activesubstances with inert carriers such as lactose or sorbitol andencapsulating the mixture in gelatine capsules.

Suitable suppositories may be produced, for example, by mixing theactive substances or combinations of active substances envisagedtherefore with conventional carriers such as neutral fats orpolyethylene glycol or the derivatives thereof.

EXAMPLES OF FORMULATION

    ______________________________________                                        1. Tablets                                                                    ______________________________________                                        Compound according to Example 3                                                                        10.0   mg                                            Corn starch              99.0   mg                                            sec. calcium phosphate   140.0  mg                                            Magnesium stearate       1.0    mg                                                                     250.0  mg                                            ______________________________________                                    

The ingredients are processed in the usual way to produce tabletsweighing 250 mg.

    ______________________________________                                        2. Capsules                                                                   ______________________________________                                        Compound according to Example 1                                                                        150.0  mg                                            Corn starch              150.0  mg                                                                     300.0  mg                                            ______________________________________                                    

The finely powdered components are thoroughly mixed. 300 mg batches ofthe mixture are packed into conventional gelatine capsules.

The compounds according to the invention are also suitable for combiningwith other pharmacodynamically active substances such as diuretics,β-adrenolytics, calcium antagonists or tranquilizers.

The following Examples illustrate the invention without restricting it.

EXAMPLES OF PREPARATION EXAMPLE 1[1-[2,6-Dimethyl-4-(2-m-tolyloxyacetylamino)-phenoxy]-2-hydroxy-3-diethylamino-propane]hydrochloride

5 g (0.015 mol) of1-[2,6-Dimethyl-4-(2-m-tolyloxyacetylamino)-phenoxy]-2,3-oxirane aredissolved in 80 ml of ethanol, 21 ml (0.02 mol) of diethylamine areadded and the mixture is refluxed for 1.5 hours at the boiling point.After the solvent has been distilled off, the residue is dissolved indilute hydrochloric acid and extracted with ether. The aqueous phase ismade alkaline with 20% sodium hydroxide solution, extracted withmethylene chloride and the organic phase is dried over sodium sulphate.The solvent is distilled off and the residue remaining is purified overa silica gel column (ethyl acetate/isopropanol/ ammonia in the ratio70:30:2). The uniform substance isolated is dissolved in acetonitrileand the hydrochloride is crystallised out by the addition of etherealhydrochloric acid and ether. The crystals are recrystallized fromethanol with the addition of ether.

Yield: 6.7 g, m.p. 159°-160° C.

EXAMPLE 2[1-[2,6-Dimethyl-4-(2-m-tolyloxyacetylamino)-phenoxy]-2-hydroxy-3-piperidino-propane]hydrochloride

6 g (0.018 mol) of1-[2,6-Dimethyl-4-(2-m-tolyloxyacetylamino)-phenoxy]propan-2,3-oxiraneare dissolved in 100 ml of ethanol and after the addition of 2 ml (0.02mol) of piperidine the mixture is refluxed for 2 hours at the boilingpoint. The ethanol is distilled off, the residue is dissolved in dilutehydrochloric acid, extracted with ether and made alkaline with sodiumhydroxide solution. The base precipitated is taken up in methylenechloride, the organic phase is dried over sodium sulphate and thesolvent is distilled off. The base is purified over a silica gel columnas in Example 1. The pure substance is dissolved in acetonitrile,ethereal hydrochloric acid is added and then ether is added untilcrystallization begins. The colourless hydrochloride is dissolved inacetonitrile and brought to crystallization by the addition of ether.

Yield: 5.8 g, m.p.: 189°-190° C.

EXAMPLE 3[1-[2,6-Dimethyl-4-(2-(2,6-dimethyl-phenoxy)-acetylamino)-phenoxy]-2-hydroxy-3-diethylamino-propan]hydrochloride

38.8 g of[1-[2,6-dimethyl-4-()2-(2,6-dimethyl-phenoxy)-acetylamino)-phenoxy]-2,3-oxiraneare dissolved in 300 ml of ethanol and after the addition of 40 ml ofdiethylamine the mixture is refluxed for two hours at the boiling point.After the ethanol has been distilled off, the residue remaining isacidified with dilute hydrochloric acid and extracted with ether. Theaqueous phase is made alkaline with dilute sodium hydroxide solution,the base precipitated is taken up in ether and the organic phase isdried over sodium sulphate. The ether is distilled off, the residue ispurified over a silica gel column (ethylacetate/isopropanol/ammonia inthe radio 70:30:5). The pure substance is dissolved in acetonitrile,ethereal hydrochloric acid and then ether are added, as a result ofwhich the hydrochloride is precipitated in crystalline form. Crystalsare dissolved in acetonitrile and ether is added until crystallizationbegins. 28.6 g of colourless crystals are obtained.

M.P 167°-168° C.

The compounds of formula I listed in Tables I to III are synthesizedanalogously to the above Examples. Unless otherwise stated, the meltingpoints are given for the hydrochlorides.

The compounds in Table I correspond to the formula ##STR6##

                                      TABLE I                                     __________________________________________________________________________    Exam-                                                                         ple R.sub.1        R.sub.2                                                                           R.sub.3                                                                           R.sub.4     R.sub.5            m.p.°C.      __________________________________________________________________________     4                                                                                               2-CH.sub.3                                                                        6-CH.sub.3                                                                        CH.sub.3    CH.sub.3           152-153 (Base)       5  "              "   "   CH.sub.2CH.sub.2 OH                                                                       CH.sub.2CH.sub.2 OH                                                                              97-99                6  "              "   "   C.sub.3 H.sub.7                                                                           C.sub.3 H.sub.7    126-128              7  "              "   "   C.sub.2 H.sub.5                                                                           C.sub.3 H.sub.7    128-131              8  "              "   "   isoC.sub.3 H.sub.7                                                                        isoC.sub.3 H.sub.7 128-130              9  "              "   "   CH.sub.3    isoC.sub.3 H.sub.7 110-112             10  "              "   "   C.sub.4 H.sub.9                                                                           C.sub.4 H.sub.9    88-90               11  "              "   "   secC.sub.4 H.sub.9                                                                        secC.sub.4 H.sub.                                                                                72-73                                                                         (Base)              12  "              "   "   CH.sub.3    C.sub.3 H.sub.7    129-131             13  "              "   "   CH.sub.3    C.sub.2 H.sub.5    138-139             14  "              "   "   CH.sub.2CHCH.sub.2                                                                        CH.sub.2CHCH.sub.2 122-123             15  "              "   "   CH.sub.3                                                                                   ##STR7##          76-79               16  "              "   "   CH.sub.3                                                                                   ##STR8##          83-86               17  "              "   "   CH.sub.3                                                                                   ##STR9##          70-74               18  "              "   "   CH.sub.3                                                                                   ##STR10##         71-75               19  "              "   "   CH.sub.3                                                                                   ##STR11##         79-82               20                                                                                 ##STR12##     2-CH.sub.3                                                                        6-CH.sub.3                                                                        H                                                                                          ##STR13##         127-130 (Base)      21  "              "   "   C.sub.2 H.sub.5                                                                           "                  90-94               22  "              "   "   isoC.sub.3 H.sub.7                                                                        "                  82-85               23  "              "   "   CH.sub.3    "                  80-84               24                                                                                 ##STR14##     "   "   CH.sub.3    CH.sub.3           viscous oil         25  "              "   "   C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5    "                   26                                                                                 ##STR15##     "   "   CH.sub.3    CH.sub.3           "                   27  "              "   "   C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5    "                   28                                                                                 ##STR16##     "   "   CH.sub.3    CH.sub.3           117-118 (Base)      29  "              "   "   C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5    101-102                                                                       (Base)              30  "              "   "   CH.sub.2CH.sub.2 OH                                                                       CH.sub.2CH.sub.2 OH                                                                              104-107             31                                                                                 ##STR17##     2-Cl                                                                              6-Cl                                                                              CH.sub.3    CH.sub.3           122-123 (Base)      32  "              "   "   CH.sub.2 H.sub.5                                                                          C.sub.2 H.sub.5    viscous                                                                       oil                 33  "              "   "   C.sub.2CH.sub.2 OH                                                                        CH.sub.2CH.sub.2 OH                                                                              158-159             34                                                                                 ##STR18##     2-CH.sub.3                                                                        6-CH.sub.3                                                                        CH.sub.3    CH.sub.3           171-172             35  "              "   "   CH.sub.2CH.sub.2 OH                                                                       CH.sub.2CH.sub.2 OH                                                                              102-103                                                                       (Base)              36                                                                                 ##STR19##     2-Cl                                                                              6-Cl                                                                              CH.sub.3    CH.sub.3           91-93 (Base)        37  "              "   "   C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5    98-99                                                                         (Base)              38  "              "   "   CH.sub.CH.sub.2 OH                                                                        CH.sub.2CH.sub.2 OH                                                                              139-141                                                                       (oxalate)           39                                                                                 ##STR20##     "   "   "           "                  149-151             40                                                                                 ##STR21##     2-CH.sub.3                                                                        6-CH.sub.3                                                                        CH.sub.3    CH.sub.3           190-191             41  "              "   "   C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5    167-168             42                                                                                 ##STR22##     2-CH.sub.3                                                                        6-CH.sub.3                                                                        CH.sub.2CH.sub.2 OH                                                                       CH.sub.2CH.sub.2 OH                                                                              164-166             43  "              "   "                                                                                  ##STR23##                                                                                 ##STR24##         86-89 (Base)        44  "              "   "   CH.sub.3                                                                                   ##STR25##         81-84               45  "              "   "   CH.sub.3                                                                                   ##STR26##         78-81               46  "              "   "   CH.sub.3                                                                                   ##STR27##         117-120                                                                       (oxalate)           47  "              "   "   CH.sub.3                                                                                   ##STR28##         84-87               48  "              "   "   CH.sub.3                                                                                   ##STR29##         75-78               49                                                                                 ##STR30##     2-CN                                                                              H   CH.sub.3    CH.sub.3           89-91 (Base)        50  "              "   "   C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5    128- 130                                                                      (Base)              51                                                                                 ##STR31##     2-Cl                                                                              6-Cl                                                                              CH.sub.3    CH.sub.3           232-234             52  "              "   "   CH.sub.2CH.sub.2 OH                                                                       CH.sub.2CH.sub.2 OH                                                                              158-159                                                                       (Base)              53                                                                                 ##STR32##     2-CN                                                                              "   CH.sub.3    CH.sub.3           138-143             54                                                                                 ##STR33##     2-Cl                                                                              6-Cl                                                                              CH.sub.3    CH.sub.3           73-74 (Base)        55  "              "   "   C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5    viscous                                                                       oil                 56  "              "   "   CH.sub.2CH.sub.2 OH                                                                       CH.sub.2CH.sub.2 OH                                                                               98-101             57                                                                                 ##STR34##     2-CH.sub.3                                                                        6-CH.sub.3                                                                        CH.sub.3    CH.sub.3           203-206             58  "              "   "   C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5    147-150             59                                                                                 ##STR35##     2-Cl                                                                              6-Cl                                                                              CH.sub.3    CH.sub.3           103-104 (Base)      60  "              "   "   C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5    72-74                                                                         (Base)              61  "              "   "                                                                                  ##STR36##                                                                                 ##STR37##         97-99 (oxalate)                                                               9                   62                                                                                 ##STR38##     2-CH.sub.3                                                                        6-CH.sub.3                                                                        C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5    166-167             63  "              "   "   CH.sub.3    CH.sub.3           158-159             64  "              "   "   C.sub.3 H.sub.7                                                                           C.sub.3 H.sub.7    157-158             65                                                                                 ##STR39##     "   "   C.sub.3 H.sub.7                                                                           C.sub.3 H.sub.7    183-184 (Base)      66  "              "   "   C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5    168-169                                                                       (Base)              67                                                                                 ##STR40##     "   "   CH.sub.3    CH.sub.3           180-181 (Base)      68                                                                                 ##STR41##     "   "   C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5    160-163 (Base)      69  "              "   "   CH.sub.3    CH.sub.3           183-185                                                                       (Base)              70  "              "   "   C.sub.3 H.sub.7                                                                           C.sub.3 H.sub.7    172-173                                                                       (Base)              71                                                                                 ##STR42##     "   "   C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5    180-181 (Base)      72  "              "   "   C.sub.3 H.sub.7                                                                           C.sub.3 H.sub.7    179-181                                                                       (Base)              73  "              "   "   CH.sub.3    CH.sub.3           211-213                                                                       (Base)              74                                                                                 ##STR43##     2-Cl                                                                              H   C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5    183-144                                                                       (Oxalate)           75                                                                                 ##STR44##     "   "   "           "                  155-157             76                                                                                 ##STR45##     "   "   CH.sub.3    CH.sub.3           149-150                                                                       (Oxalate)           77                                                                                 ##STR46##     "   "   "           "                  190-191                                                                       (Oxalate)           __________________________________________________________________________

Other compounds of formula ##STR47## according to the invention arelisted in Table II.

                                      TABLE II                                    __________________________________________________________________________     Example                                                                            R.sub.1     R.sub.2                                                                           R.sub.3                                                                           ##STR48##  m.p. °C.                          __________________________________________________________________________    78                                                                                  ##STR49##  2-CH.sub.3                                                                        6-CH.sub.3                                                                         ##STR50## 190-191                                   79   "           "   "                                                                                  ##STR51## 146-147 (Base)                            80   "           "   "                                                                                  ##STR52## 162-164                                   81                                                                                  ##STR53##  2-CN                                                                              H                                                                                  ##STR54## 244-246                                   __________________________________________________________________________

Table III

The compounds included in this Table according to the inventioncorrespond to the formula

    __________________________________________________________________________     ##STR55##                                                                    Example                                                                             R.sub.1     R.sub.2                                                                            R.sub.3                                                                           R.sub.4                                                                             R.sub.5                                                                            m.p. °C.                         __________________________________________________________________________    82                                                                                   ##STR56##  H    H    CH.sub.3                                                                           CH.sub.3                                                                           150-2                                   83    "           H    H    i-C.sub.3 H.sub.7                                                                  H    144-6                                   84    "           H    H    C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    111-2                                   85    "           H    H    n-C.sub.3 H.sub.7                                                                  H    114-5                                   86                                                                                   ##STR57##  H    H    i-C.sub.3 H.sub.7                                                                  H    184-5                                   87    "           H    H    CH.sub.3                                                                           CH.sub.3                                                                           171-3                                   88    "           H    H    n-C.sub.3 H.sub.7                                                                  H    157-8                                   89                                                                                   ##STR58##  H    H    C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    136-8                                   90                                                                                   ##STR59##  H    H    t-C.sub.4 H.sub.9                                                                  H    159-60                                  91                                                                                   ##STR60##  6-CH.sub.3                                                                         H    C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    150-1                                   92                                                                                   ##STR61##  H    H    CH.sub.3                                                                           CH.sub.3                                                                           124-5 (Oxalate)                         93                                                                                   ##STR62##  6-CH.sub.3                                                                         H    i-C.sub.3 H.sub.7                                                                  CH.sub.3                                                                           156-7                                   94    "           6-CH.sub.3                                                                         H    CH.sub.3                                                                           CH.sub.3                                                                            146-8                                                                        (Oxalate)                               95    "           6-CH.sub.3                                                                         H    t-C.sub.4 H.sub.9                                                                  H    169-70                                  96    "           H    H    t-C.sub.4 H.sub.9                                                                  H    180-1                                   97                                                                                   ##STR63##  H    H    C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    139-40                                  98                                                                                   ##STR64##  H    H    n-C.sub.3 H.sub.7                                                                  H    145-14 7 (Oxlate)                       99    "           H    H    t-C.sub.4 H.sub.9                                                                  H    157-9                                   100   "           H    H    i-C.sub.3 H.sub.7                                                                  H    132-3                                   101                                                                                  ##STR65##  6-CH.sub.3                                                                         H    n-C.sub.3 H.sub.7                                                                  H    101-2                                   102                                                                                  ##STR66##  6-CH.sub.3                                                                         H    C.sub.2 H.sub.5                                                                    C.sub.2 H.sub. 5                                                                   113-50                                  103   "           6-CH.sub.3                                                                         H    i-C.sub.3 H.sub.7                                                                  H    153-6                                   104   "           6-CH.sub.3                                                                         H    CH.sub.3                                                                           CH.sub.3                                                                           122-3                                   105   "           6-CH.sub.3                                                                         H    t-C.sub.4 H.sub.9                                                                  H    189-91                                  106   "           6-CH.sub.3                                                                         H    n-C.sub.3 H.sub.7                                                                  H    128-30                                  107                                                                                  ##STR67##  6-CH.sub.3                                                                         H    C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    146-8                                   108   "           6-CH.sub.3                                                                         H    t-C.sub.4 H.sub.9                                                                  H    130-2                                   109   "           6-CH.sub.3                                                                         H    i-C.sub.3 H.sub.7                                                                  H    152-4                                                                         (Oxalate)                               110   "           6-CH.sub.3                                                                         H    CH.sub.3                                                                           CH.sub.3                                                                           132-3                                                                         (Oxalate)                               111   "           6-CH.sub.3                                                                         6-CH.sub.3                                                                         C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                              112   "           3-CH.sub.3                                                                         H    C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                              113                                                                                  ##STR68##  4-CH.sub.3                                                                         6-CH.sub.3                                                                         C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                              114   "           5-CH.sub.3                                                                         H    C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                              115                                                                                  ##STR69##  4-CH.sub.3                                                                         6-CH.sub.3                                                                         CH.sub.3                                                                           n-C.sub.3 H.sub.7                            __________________________________________________________________________

Pharmacological trials

The compounds according to the invention were investigated according toC. Lillie et al., Drug Research 35, 301-305 (1985).

Isolated guinea pig hearts according to Langendorff, moist weight1.0-1.2 g, perfused with standard tyrode (31° C., saturated with O₂ +2%CO₂) under constant pressure (60 cm H₂ O). After destruction of thesinus node region at the right atrium, electrical ventricularstimulation with rectangular pulses (1 mA, 10 msec) at 2.5 Hz. Bias 2 g,contractions recorded isometrically.

Perfusion with tyrode containing the test substance (concentration givenin mcg ml) was carried out for 30 min.

The table given the changes as a percentage of the previous values (Δ%)of the ECG parameters of ST and QRS and the contraction amplitude andthe throughflow at the end of the period of perfusion with the tyrodecontaining the test substance. po The results for some of the compoundstested are shown in the following Table.

    ______________________________________                                                                     changes (Δ%) after 0 min.                  Compound mcg/ml   ST    QRS  contractility throughflow                        ______________________________________                                        Example  1                                                                             1        +39   +4   -31       +5                                     Example 12                                                                             1        +38   +5   -23       -2                                     Example 41                                                                             1        +31   +2   -9        +5                                     ______________________________________                                    

As the values in the Table show, the ST level is significantlyincreased, as desired, but the QRS level and the throughflow are onlyslightly increased.

What is claimed is:
 1. A compound of formula ##STR70## wherein R₁represents a phenyl group which may optionally be substituted by one ormore halogen atoms, lower alkyl, alkoxy, alkenyl, alkynyl, alkenyloxy,alkynyloxy, cycloalkyl, acyl, acyloxy, alkoxycarbonyl, hydroxyalkyl oralkoxyalkyl groups or a sulphamoyl group, or it may represent anaryloxyalkyl group which may optionally be substituted by one or morehalogen atoms, lower alkyl, alkoxy, alkenyl, alkynyl, alkenyloxy,alkynyloxy, hydroxyalkyl, alkoxyalkyl, acyl, acyloxy or alkoxycarbonylgroups,R₂ represents a halogen atom, an alkyl or alkoxy group with 1 to4 carbon atoms or a CN group, R₃ represents a halogen atom or an alkylgroup with 1 to 4 carbon atoms, R₄ represents a straight-chained orbranched alkyl group with 1 to 10 carbon atoms or a hydroxylakyl groupwith 2 to 5 carbon atoms, and R₅ represents a straight-chained orbranched alkyl group with 1 to 10 carbon atoms or a hydroxylakyl groupwith 2 to 5 carbon atoms or a phenylalkyl group or a phenoxyalkyl group,whilst the aromatic pat may be substituted by alkyl or alkoxy groups orby chlorine or bromine atoms, or a pharmaceutically acceptable acidaddition salt thereof.
 2. A compound as claimed in claim 1, wherein R₁is a substituted phenoxymethyl group, R₂ and R₃ represent halogen, cyanoor methyl, and one of them may also represent hydrogen, and R₄ and R₅represent lower straight-chained or branched alkyl groups.
 3. Acompounds as claimed in claim 1 or 2, wherein R₁ --CO--NH is in the4-position of the phenoxy group, R₁ represents a phenoxymethyl group,mono- or disubstituted by methyl,R₂ and R₃ represent chlorine or methyl,and R₄ and R₅ represent methyl, ethyl, n-propyl or i-propyl, wherein R₂/R₃ and R₄ /R₅ may be identical or different. 4.[1-[2,6-Dimethyl-4-(2-m-tolyloxyacetylamino)phenoxy]-2-hydroxy-3-diethylamino-propane]hydrochlorideor a pharmaceutically acceptable acid addition salt thereof. 5.[1-[2,6-Dimethyl-4-(2-(2,6-dimethyl-phenoxy)-acetylamino)-phenoxy]-2-hydroxy-3-diethylamino-propan]hydrochlorideor a pharmaceutically acceptable acid addition salt thereof. 6.1-[2,6-Dimethyl-4-[2-(3-methylphenoxy)-acetylamino]phenoxy]-2-hydroxy-3-methyl-n-propylaminopropaneor a pharmaceutically acceptable acid addition salt thereof.
 7. Apharmaceutical composition comprising a compound as claimed in claim 1together with conventional excipients and/or carriers.
 8. A method fortreating cardiac arrhythmia, tachycardia or high blood pressure whichcomprises administering an antiarrhythmic, bradycardiac or hypotensiveamount of a compound according to claims 1,2,3,4,5 or 6.